Epidemiology studies have documented frequent hypomagnesemia in the elderly who also have a high cancer incidence. Anticancer drugs (eg. cisplatin, caboplatin) may cause hypomagnesemia and cardiovascular complications such as arrhythmias. EGFR inhibiting antibody (cetuximab) and TKI (erlotinib) drugs are anticancer agents, and the former is well known to produce hypomagnesemia. Recently, FDA approved-erlotinib has been reported to cause hypomagnesemia in mice, and a higher clinical incidence of gastrointestinal (GI) side effects. Our pilot study has shown significant hypomagnesemia and early systolic dysfunction in rats treated with the TKI drug, tyrphostin. Our prior animal studies demonstrated that diet-induced hypomagnesemia can trigger a significant production/release of substance P (SP) with resultant intestinal (endotoxemia) toxicity and cardiac dysfunction (decreased % FS & LVEF). Therefore, we propose that SP- induced inflammation due to hypomagnesemia may be a key mediator of the GI side effects and potential cardiovascular toxicity in some patients treated with erlotinib. The specific aims are: 1) Determine the extent of chronic erlotinib treatment-induced hypomagnesemia and subsequent intestinal and cardiac inflammation/dysfunction in rats; and 2) Assess if long-term erlotinib-induced intestinal and cardiac toxicity can be attenuated by the clinically-used SP receptor blocker, aprepitant (Emend), and if it is effective in erlotinib-treated animals with co-existing hypomagnesemia (as a paradigm for age- or Mg-wasting drug-related hypomagnesemia). Since oral Mg replacement therapy may prove ineffective in prolonged hypomagnesemia, particularly in patients with GI side effects, the outcome of this project may have immediate clinical implications for treatment of GI and potential cardiac side effects in cancer patients treated with EGFR/TKI drugs, particularly when combined with cisplatin. PUBLIC HEALTH RELEVANCE: Hypomagnesemia is a condition commonly seen in the elderly population, and it may become aggravated by anticancer drugs, which have magnesium-wasting side effects. Our experimental findings with animal models have shown that hypomagnesemia can induce the release of substance P (SP), which can trigger a cascade of inflammatory/oxidative events that will ultimately lead to the development of increased intestinal permeability, cardiomyopathy and contractile dysfunction. We submit that agents that block SP activity may protect patients against hypomagnesemia-related side effects resulting from prolonged use of some chemotherapy drugs.